The human immune response to infection and immunization - Profiling via modern immunological methods and systems biology. The Hepatitis B subunit vaccine induces immunity in millions of people by inducing antibodies that prevent viral infection. However, the variability in the antibody response to the Hepatitis B surface antigen (HBS) component of the vaccine in different individuals is remarkably large and some individuals fail to respond altogether. We propose that this variability provides a golden opportunity to understand the diversity of human immune responses to vaccination and identify immune response correlates. The central hypothesis of this application is that the number of naive antigen-specific B cells and/or CD4+ helper T cells in the pre-immune repertoire dictates the magnitude of the antibody response. We will test this hypothesis using an ultra sensitive method that we developed to detect HBS-specific B cells and HBS peptide-Major Histocompatibilty Complex II-specific CD4+ helper T cells in humans before and after vaccination. The goals of this proposal are to develop the reagents needed for comprehensive analysis of the HBS-specific naive T and B cells in humans and then use these tools to determine whether or not the great range in postvaccination antibody titer is explained by variations in the pre-immune repertoire. This innovative approach could provide the ultimate biomarker of vaccine response - the vaccine-specific lymphocytes themselves - and provide direction as to how the vaccine could be improved to protect all individuals. PUBLIC HEALTH RELEVANCE: These studies are relevant because they have the potential to explain why certain people do not develop specific antibodies after receiving the Hepatitis B subunit vaccine. Our theory is that these individuals lack the relevant lymphocytes before vaccination. If this theory is correct, then these individuals should develop antibodies if vaccinated with a different Hepatitis B subunit. Therefore, these studies have the potential to predict who will not respond to this important vaccine and suggest a solution to this problem.